Native CD4 T-cells can differentiate upon activation into either Th1 or Th2 cells, which have significantly different immune functions based on the cytokines they produce. Th1 cells promote type 1 immunity, producing IFN-γ which drives cell-mediated immunity and IgG2A synthesis. Th2 cells enhance type 2 immunity by producing IL-4, IL-5, and IL-13 and promoting antibody-mediated responses and class switching to IgG1 and IgE. These immune responses can be detrimental when they are not appropriately regulated, as in autoimmune diseases, or when excessive, as in allergic diseases.
The Th1 differentiation pathway is normally stimulated in response to infectious microbes that activate macrophages and/or NK cells. These include bacteria, some parasites, viruses and certain foreign antigens. A common feature of these antigens is that they elicit innate immune reactions with the production of IL-12. IL-12 binds to receptors on antigen-stimulated CD4+ cells and activates the transcriptional factor STAT-4. Subsequently, STAT-4 promotes the differentiation of the T-cells into Th1 cells. A transcription factor called T-bet also plays a critical role in Th1 development. T-bet is induced by IFN-α and provides an amplification of the Th1 responses. Th1 cells secrete IFN-γ, lymphotoxin (LT), and TNF. IFN-γ acts on macrophages to increase phagocytosis and promote killing of microorganism in phagolysomes and on B lymphocytes to stimulate production of IgG antibodies that opsonize microbes and other antigens for phagocytosis. LT and TNF activate neutrophils and stimulate inflammation. IL-2 is an autocrine growth factor made by Th1 cells.
Th2 differentiation normally occurs in response to helminths and allergens. Host response to these antigens can cause chronic T-cell stimulation, often without a significant innate immune response or macrophage activation. The differentiation of antigen-stimulated T-cells to the Th2 subset is dependent on IL-4, which functions by activating STAT-6. STAT-6, similar to STAT-4, is a transcriptional factor that stimulates Th2 development. Another transcription factor called GATA-3 also plays an important role in Th2 development by activating transcription of Th2-specific cytokine genes. Th2 cells secrete IL-4 and IL-5. IL-4 acts on B-cells to stimulate production of antibodies that bind to mast cells, such as IgE. IL-4 is also an autocrine growth and differentiation cytokine for Th2 cells. IL-5 activates eosinophils, primarily a defense against parasitic infections. Th2 cytokines also inhibit both classical macrophage activation and Th1-mediated reactions.
Allergy is classified as a Type I hypersensitivity reaction, also known as an immediate-type hypersensitivity reaction, and is stimulated by Th2-mediated production of IgE. Th2 cells can promote antibody isotype switching of B-cells from IgM to IgE. IgE can be produced by plasma cells located in the lymph nodes draining from the site of antigen entry or peripherally produced at the local site of allergic reaction. IgE sensitizes mast cells and basophils by binding to the high-affinity receptor for IgE (FcεRI) expressed on their surface. Upon allergen-mediated crosslinking of the IgE-FcεR1 complex, mast cells and basophils degranulate to release vasoactive amines (primarily histamine), lipid mediators (prostaglandins and cysteinyl leukotrienes), cytokines and chemokines, all of which characterize the immediate phase of the allergic reaction. Histamine is one of the key factors of the immediate phase of the allergic reaction, regulating dendritic cells, T cells and antibody isotype class-switching via four distinct histamine receptors (HR). HR2 acts as an anti-inflammatory and anti-allergic receptor, whereas HR1, HR3 and HR4 show proinflammatory effects. Mast cells are not only associated with type-I hypersensitivity reactions but also play a role in chronic inflammation. IgE also binds FcεR1 on the surface of dendritic cells and monocytes and binds FcεRII on the surface of B-cells. These interactions enhance the uptake of allergens by these antigen-presenting cells and the subsequent presentation of allergen-derived peptides to specific CD4+ T-cells, which drive the late phase of the allergic reaction. Treatment with anti-IgE monoclonal antibody significantly reduces allergen-induced late-phase responses, demonstrating the role of IgE in enhancing T-cell responses to allergens.
After allergen exposure, increased levels of histamine and tryptase can be detected in the bronchoalveolar lavage in allergic-asthma, in nasal washes in rhinitis, in tears in conjunctivitis and the circulatory system in systemic anaphylaxis. In the lower airways, the primary targets for mast cell mediators are the secretory glands, blood vessels, and bronchial smooth muscle. Bronchoconstriction is the main clinical manifestation of early phase responses in allergic-asthma, manifested by a decrease in forced expiratory volume in 1 second (FEV1) within 1 hour of allergen exposure. In the nasal mucosa, the potential targets for mast cell mediators are the mucus glands, nerves, blood vessels, and venous sinuses. The clinical manifestation of early phase responses in the upper airway are itching, sneezing, nasal obstruction, and watery discharge. Typically early phase responses resolve within an hour.
The late phase response develops as a result of cytokines and chemokines generated by resident inflammatory cells, such as mast cells, macrophages, and eosinophils. Although mast cells are not essential for the late phase response, the detection of IL-5, IL-6, IL-13 and TNF-α in mast cells, and their release after the cross-linking of IgE supports roles for both IgE and mast cells in ensuring persistent allergic inflammation and hyperresponsiveness. In chronic allergic inflammations of lung and skin, the subepithelial tissue turns into a secondary lymphoid organ-like tissue with the infiltration of T-cells, dendritic cells and B-cells. Activated T-cells interact with resident tissue cells as well as with other migrating inflammatory cells. They activate bronchial epithelial cells, smooth muscle cells, macrophages, fibroblasts in the chronic-asthmatic lungs, and epidermal keratinocytes in the allergic skin Resident tissue cells contribute to inflammation by secretion of pro-inflammatory cytokines and chemokines. Production of IFN-γ and TNF-α together with expression of FAS-ligand by Th1 cells leads to epithelial cell activation followed by apoptosis, and compromises barrier function of epithelial cells in the lungs and the skin. This involves two stages. First, the pro-inflammatory stage with activation of epithelial cells and the release of chemokines and pro-inflammatory cytokines. This is followed by the eventual death of keratinocytes and bronchial epithelial cells, which leads to a visible pathology including epithelial desquamation in chronic-asthma and epidermal spongiosis in eczema.
Antibody-mediated destruction of host cells is an uncommon side-effect associated with in the intake of certain drugs, such as the antibiotic penicillin These are Type II hypersensitivity reactions in which the drug binds to the cell surface and serves as a target for anti-drug IgG antibodies and subsequently promote destruction of the cell. The anti-drug antibodies are only produced in a minority of the population, and it is not well understood why these antibodies are generated in these individuals. The cell-bound antibody triggers clearance of the cell from the circulation, predominantly by tissue macrophages in the spleen, which bear Fcγ receptors.
Type III hypersensitivity reactions can arise with soluble antigens. The pathology is caused by the deposition of antigen-antibody aggregates or immune complexes within particular tissues and organ sites Immune complexes are generated in all antibody responses but their pathogenic potential is determined, in part, by their size, and the amount, affinity, and isotype of the responding antibody. Larger aggregates fix complement and are readily cleared from the circulation by the mononuclear phagocyte system. However, small complexes that form tend to deposit in blood vessels walls. There they can ligate Fc receptors on leukocytes, leading to leukocyte activation and tissue injury.
Type IV hypersensitivity reactions are usually stimulated by soluble antigens and result in chronic inflammatory disorders, like chronic-asthma and chronic allergic rhinitis. An important feature of asthma is chronic inflammation of the airways, which is characterized by the continued presence of increased numbers of Th2 lymphocytes, eosinophils, neutrophils, and other leukocytes. These cells stimulate increased mucus secretion. The direct action of Th2 cytokines such as IL-9 and IL-13 on airway epithelial cells may have a role on the induction of goblet-cell metaplasia and the secretion of mucus.
Most immediate hypersensitivity disorders are associated with excessive Th2 responses to normally innocuous environmental antigens. These disorders predominate in most industrial countries and are a growing healthcare concern in developing nations. There are numerous medicaments to treat or alleviate the symptoms associated hypersensitive diseases, including systemic therapies as well as more localized treatments. Local therapeutics are most often prescribed to achieve the maximum effect at the site of disease while minimizing the possibility of systemic side-effects. These local treatments are generally administered topically or by aerosol/spray, including alpha-adrenergic decongestants, adrenergic bronchodilators, antihistamines, and corticosteroids. Unfortunately, many of these drugs still have the disadvantage of producing unwanted side-effects even when administered locally. As many patients use excessive quantities of these drugs to relieve symptoms quickly, there is an increased risk that the patient will suffer deleterious effects. Therefore, a need remains for developing more effective treatments for the underlying causes of hypersensitivity responses.